Cross-presentation of glycoprotein 96-associated antigens on major histocompatibility complex class I molecules requires receptor-mediated endocytosis

被引:289
作者
Singh-Jasuja, H
Toes, REM
Spee, P
Münz, C
Hilf, N
Schoenberger, SP
Ricciardi-Castagnoli, P
Neefjes, J
Rammensee, HG
Arnold-Schild, D
Schild, H
机构
[1] Univ Tubingen, Inst Cell Biol, Dept Immunol, D-72076 Tubingen, Germany
[2] Leiden Univ, Med Ctr, Dept Immunohaematol, NL-2300 RC Leiden, Netherlands
[3] Leiden Univ, Med Ctr, Transfus Bank, NL-2300 RC Leiden, Netherlands
[4] Netherlands Canc Inst, Div Tumor Biol, NL-1066 CX Amsterdam, Netherlands
[5] Rockefeller Univ, Cellular Physiol & Immunol Lab, New York, NY 10021 USA
[6] Univ Milano Bicocca, Dept Biotechnol & Biosci, I-20126 Milan, Italy
关键词
heat shook protein-peptide complex; cross-priming; receptor-mediated endocytosis; cytotoxic T lymphocyte activation; dendritic cell;
D O I
10.1084/jem.191.11.1965
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Heat shock proteins (HSPs) like glycoprotein (gp)96 (glucose-regulated protein 94 [grp94]) are able to induce specific cytotoxic T lymphocyte (CTL) responses against cells from which they originate. Here, we demonstrate that for CTL activation by gp96-chaperoned peptides, specific receptor-mediated uptake of gp96 by antigen-presenting cells (APCs) is required. Moreover, we show that in both humans and mice, only professional APCs like dendritic cells (DCs), macrophages, and B cells, but not T cells, are able to bind gp96, The binding is saturable and can be inhibited using unlabeled gp96 molecules. Receptor binding by APCs leads to a rapid internalization of gp96, which colocalizes with endocytosed major histocompatibility complex (MHC) class I and class II molecules in endosomal compartments. Incubation of gp96 molecules isolated from cells expressing an adenovirus type 5 E1B epitope with the DC line D1 results in the activation of E1D-specific CTLs. This CTL activation can be specifically inhibited by the addition of irrelevant gp96 molecules not associated with E1B peptides. Our results demonstrate that only receptor-mediated endocytosis of gp96 molecules leads to MHC class I-restricted re-presentation of gp96-associated peptides and CTL activation, non-receptor-mediated, nonspecific endocytosis is not able to do so. Thus, we provide evidence on the mechanisms by which gp96 is participating in the cross-presentation of antigens from cellular origin.
引用
收藏
页码:1965 / 1974
页数:10
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